PMID- 26921863 OWN - NLM STAT- MEDLINE DCOM- 20161213 LR - 20181202 IS - 1573-2517 (Electronic) IS - 0165-0327 (Linking) VI - 196 DP - 2016 May 15 TI - Insulin receptor sensitizer, dicholine succinate, prevents both Toll-like receptor 4 (TLR4) upregulation and affective changes induced by a high-cholesterol diet in mice. PG - 109-16 LID - S0165-0327(15)30949-6 [pii] LID - 10.1016/j.jad.2016.02.045 [doi] AB - BACKGROUND: High cholesterol intake in mice induces hepatic lipid dystrophy and inflammation, signs of non-alcoholic fatty liver disease (NAFLD), depressive- and anxiety-like behaviors, and the up-regulation of brain and liver Toll-like receptor 4 (Tlr4). Here, we investigated whether dicholine succinate (DS), an insulin receptor sensitizer and mitochondrial complex II substrate would interact with these effects. METHODS: C57BL/6J mice were given a 0.2%-cholesterol diet for 3 weeks, alone or along with oral DS administration, or a control feed. Outcomes included behavioral measures of anxiety/depression, and Tlr4 and peroxisome-proliferator-activated-receptor-gamma coactivator-1b (PPARGC1b) expression. RESULTS: 50mg/kg DS treatment for 3 weeks partially ameliorated the cholesterol-induced anxiety- and depressive-like changes. Mice were next treated at the higher dose (180mg/kg), either for the 3-week period of dietary intervention, or for the last two weeks. Three-week DS administration normalized behaviors in the forced swim and O-maze tests and abolished the Tlr4 up-regulation in the brain and liver. The delayed, 2-week DS treatment had similar effects on Tlr4 expression and largely rescued the above-mentioned behaviors. Suppression of PPARGC1b, a master regulator of mitochondrial biogenesis, by the high cholesterol diet, was prevented with the 3-week administration, and markedly diminished by the a 2-week administration of DS. None of treatments prevented hepatic dystrophy and triglyceride accumulation. LIMITATIONS: Other conditions have to be tested to define possible limitations of reported effects of DS. CONCLUSIONS: DS treatment did not alter the patho-morphological substrates of NAFLD syndrome in mice, but ameliorated its molecular and behavioral consequences, likely by activating mitochondrial functions and anti-inflammatory mechanisms. CI - Copyright (c) 2016 Elsevier B.V. All rights reserved. FAU - Strekalova, Tatyana AU - Strekalova T AD - Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands. Electronic address: t.strekalova@maastrichtuniversity.nl. FAU - Costa-Nunes, Joao P AU - Costa-Nunes JP AD - Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; CEDOC, NOVA Medical School, Faculdade de Ciencias Medicas, FCM, Universidade Nova de Lisboa, Campo Martires da Patria, 130, 1169-056 Lisboa, Portugal. FAU - Veniaminova, Ekaterina AU - Veniaminova E AD - Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiyskaya 8, Moscow 125315, Russia. FAU - Kubatiev, Aslan AU - Kubatiev A AD - Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Baltiyskaya 8, Moscow 125315, Russia. FAU - Lesch, Klaus-Peter AU - Lesch KP AD - Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands; Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstr. 15, 97080 Wuerzburg, Germany. FAU - Chekhonin, Vladimir P AU - Chekhonin VP AD - Serbsky National Research Center for Social and Forensic Psychiatry, Department of Fundamental and Applied Neurobiology, per. Kropotkin 23, Moscow 119034, Russian Federation. FAU - Evans, Matthew C AU - Evans MC AD - Department of Pharmacology, Oxford University, Mansfield Road, OX1 3QT Oxford, UK. FAU - Steinbusch, Harry W M AU - Steinbusch HW AD - Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Universiteitssingel 40, 6200 MD Maastricht, The Netherlands. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160218 PL - Netherlands TA - J Affect Disord JT - Journal of affective disorders JID - 7906073 RN - 0 (Succinates) RN - 0 (Toll-Like Receptor 4) RN - 0 (Triglycerides) RN - 97C5T2UQ7J (Cholesterol) RN - EC 2.7.10.1 (Receptor, Insulin) RN - J2R869A8YF (Succinylcholine) RN - N91BDP6H0X (Choline) SB - IM MH - Animals MH - Anxiety/drug therapy/etiology MH - Cholesterol/adverse effects MH - Choline/*analogs & derivatives/pharmacology MH - Depression/drug therapy/etiology MH - Diet/adverse effects MH - Female MH - Inflammation MH - Mice MH - Mice, Inbred C57BL MH - Non-alcoholic Fatty Liver Disease/*drug therapy/etiology/psychology MH - Receptor, Insulin/*drug effects MH - Succinates/*pharmacology MH - Succinylcholine MH - Toll-Like Receptor 4/*drug effects MH - Triglycerides/metabolism MH - Up-Regulation/drug effects OTO - NOTNLM OT - Anxiety OT - Depression OT - Insulin receptor sensitizers OT - Mice OT - Toll-like receptor four (Tlr4) OT - Western diet EDAT- 2016/02/28 06:00 MHDA- 2016/12/15 06:00 CRDT- 2016/02/28 06:00 PHST- 2015/09/15 00:00 [received] PHST- 2016/02/03 00:00 [revised] PHST- 2016/02/16 00:00 [accepted] PHST- 2016/02/28 06:00 [entrez] PHST- 2016/02/28 06:00 [pubmed] PHST- 2016/12/15 06:00 [medline] AID - S0165-0327(15)30949-6 [pii] AID - 10.1016/j.jad.2016.02.045 [doi] PST - ppublish SO - J Affect Disord. 2016 May 15;196:109-16. doi: 10.1016/j.jad.2016.02.045. Epub 2016 Feb 18.